The FHIT gene encompasses the most active common fragile site at chromosome 3p14.2 (1, 2). Fhit expression is lost or reduced in a large fraction of most types of human tumors due to allelic loss, genomic rearrangement, promoter hypermethylation, or combinations thereof (3, 4). Fhit knock-out mice show increased susceptibility to cancer development (5, 6) and FHIT gene therapy prevents tumors in carcinogen-exposed Fhit-deficient mice (7, 8). Fhit restoration by stable transfection in cancer cells has little effect in vitro, unless cells are exposed to stress, including the stress of the nude mouse environment in vivo (9); viral-mediated Fhit restoration, a process that simultaneously supplies stress and Fhit expression, suppresses tumorigenesis in vivo and triggers apoptosis of many types of malignant cells in vitro (10-13), including lung cancer cells.
In lung hyperplastic lesions, DNA damage checkpoint genes are already activated, leading to selection for mutations in checkpoint proteins and neoplastic progression (14, 15). Evidence of DNA alteration at FRA3B within FHIT accompanied the hyperplasia and checkpoint activation. Loss of FHIT alleles occurs in normal appearing bronchial epithelial cells of smokers, prior to pathologic changes or alterations in expression of other suppressor genes (16-18).
Fhit expression is down-regulated by exposure to DNA damaging agents (19) and Fhit plays a role in response to such agents (20, 21), with Fhit-deficient cells escaping apoptosis and accumulating mutations.
Although Fhit expression triggers apoptosis in several experimental models through caspase-dependent mechanisms involving extrinsic and intrinsic apoptotic pathways, little is known about early events in this process and how Fhit loss is involved in tumor initiation.
Therefore, there is a need for methods for altering the expression of FHIT in subjects in need thereof. There is also a need for compositions that are useful to alter the expression of FHIT in subjects in need thereof.